Project Summary Down Syndrome (DS) model mice have three abnormalities in synaptic functions that can explain the cognitive deficits in DS: Decreased long-term potentiation (LTP) and enhanced long- term depression (LTD) of glutamatergic synapses, as well as enhanced inhibitory transmission at GABAergic synapses. Our recent published work indicates that all three observed synaptic dysfunction should be caused by the hyper-phosphorylation of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) seen in DS mice. Our recent unpublished work indicates an intriguing possible mechanism for the cause of CaMKII hyper-phosphorylation in the DS mice. Importantly, this mechanism could also be targeted by pharmacological intervention. As a proof of principle, this project will focus on two aspects of the overall question: (Aim 1) Testing the underlying cause for CaMKII hyper-phosphorylation in DS mice (using a new mutant mouse line that has been generated in the lab and that is incompetent for the proposed underlying mechanism); (Aim 2) Restoration of normal LTP by genetic reversal of T305/306 hyper-phosphorylation in DS mice (using a CaMKII T305/306AV mutant mouse line currently available to the lab). Future studies will test restoration of the other synaptic dysfunctions in DS, restoration of cognitive behavioral tasks, and restoration also by pharmacological means. Notably, while it may seem preposterous to propose a reversal of cognitive impairments in a very complex syndrome by a rather simple intervention, there is actually prior precedent for success: In a model of a different genetic condition that causes cognitive impairments, Angelman Syndrome (AS), CaMKII is also hyper-phosphorylated, and even heterozygous T305/306AV mutation was sufficient to restore both normal LTP and spatial learning. In contrast to AS, the hyper-phosphorylation of CaMKII in DS could be targeted also pharmacologically (if our hypothesized underlying mechanism is correct). Thus, this project will not only provide significant further insight into the mechanism underlying normal synaptic functions and their impairments in DS, but also has tremendous potential for directly opening a new therapeutic avenue for restoring cognitive functions in patients with DS.